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NIHR Signal The benefits and harms of aspirin for people with type 2 diabetes are finely balanced

Daily aspirin reduced the risk of serious vascular events among people with diabetes, while increasing the risk of major bleeding to a similar extent. Aspirin prevented one person in every 100 from having a heart attack or stroke over seven years, but an additional person per 100 experienced a major bleed.

The ASCEND study is one of three large placebo-controlled trials investigating the effects of 100mg daily aspirin for primary prevention in people without established cardiovascular disease. However, unlike other trials (in healthy older adults), this study found that aspirin had no effect on cancer risk during the study period.

The finding supports NICE recommendations that aspirin shouldn’t be prescribed to people with diabetes who do not have existing cardiovascular disease.

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Why was this study needed?

Cardiovascular disease is the leading cause of death in the UK. It accounted for 152,465 deaths in 2016, of which 66,076 deaths were from coronary heart disease and 37,771 from stroke. Around 4 million people in the UK have diabetes, mostly type 2. Adults with diabetes are two to three times more likely to develop cardiovascular disease, and nearly twice as likely to die from heart disease or stroke, compared with those without diabetes.

It’s well established that aspirin reduces risk in people who have already experienced a heart attack or stroke. However, use as primary prevention for people without established disease is debated. A prior study found that aspirin may slightly reduce heart disease and strokes, but the benefit was outweighed by the bleeding risk.

A group of three trials are investigating the use of aspirin for primary prevention in people with different risk factors, and ASCEND looks at those with diabetes.

What did this study do?

The ASCEND randomised controlled trial included 15,480 UK adults, aged 40 years or over, with any type of diabetes but without known cardiovascular disease. They were assigned to receive 100mg of aspirin daily or matching placebo. They were also assigned to daily capsules containing n−3 fatty acids or matching placebo, the results of which are reported in a companion publication.

Neither participants nor researchers were aware of group allocation. Baseline characteristics and adherence to treatment were equivalent in both groups. Average follow-up was 7.4 years with complete participant follow-up.

The trial had sufficient sample size to detect a 15% difference in the main outcome of a first serious vascular event, defined as a non-fatal heart attack or stroke, transient ischemic attack, or death from a vascular cause.

What did it find?

Fewer people taking aspirin experienced a serious vascular event during follow-up: 8.5% compared with 9.6% taking placebo (rate ratio [RR] 0.88, 95% confidence interval [CI] 0.79 to 0.97). There was no difference in the number of deaths from vascular causes.

However, aspirin similarly increased the number of people who experienced a major bleed: 4.1% compared with 3.2% taking placebo (RR 1.29, 95% CI 1.09 to 1.52), of which 41% were gastrointestinal bleeds. The rate of fatal bleeds was equivalent in both groups (0.2%), as was the rate of haemorrhagic stroke (0.3%).

This gave a close risk-benefit balance: about 91 people with diabetes would need to take aspirin over seven years to prevent one serious vascular event, while treating 112 would cause one major bleed. Put another way, this is approximately one in 100 people experiencing a major benefit and one in 100 people a major harm, on average.

Adjustments for baseline cardiovascular risk made no difference to the comparative rates of vascular events or serious bleeds, nor did use of n−3 fatty acids.

Aspirin did not affect cancer risk, which occurred in 12% of both groups, nor the risk of gastrointestinal cancers, specifically, affecting 2% of both groups.

What does current guidance say on this issue?

The NICE 2015 guideline on the management of type 2 diabetes states that aspirin (or other antiplatelet therapy) should not be offered to adults with type 2 diabetes who do not have cardiovascular disease.

The NICE guideline on cardiovascular disease risk assessment and reduction, recommends using the QRISK2 assessment tool in assessing need for primary prevention in people with type 2 diabetes. Those who score 10% are offered statins in addition to weight management and lifestyle modifications (to diet, physical activity, smoking and alcohol).

In the NICE 2013 guideline on myocardial infarction, daily aspirin is recommended indefinitely as secondary prevention among people who have had an acute coronary syndrome.

What are the implications?

Aspirin protects against further cardiovascular events in people with established cardiovascular disease. Yet despite an increased risk of heart disease and stroke, most people with early diabetes live without these conditions.

But does using aspirin as prevention help these people? The large sample size and long-term follow-up appear to produce a definitive answer. The small benefit of aspirin for primary cardiovascular prevention in diabetes is offset by an equivalent small risk of serious bleeding.

The evidence supports guideline recommendations that aspirin should not be prescribed for primary prevention of cardiovascular disease. Diabetes alone is not sufficient indication. Lifestyle modifications and use of statins, if indicated, should be used to reduce risk.

Citation and Funding

This project was funded by the British Heart Foundation. The aspirin and matching placebo (along with funding for packaging) were provided by Bayer (Germany), while Solvay, Abbott, and Mylan provided the n−3 fatty acid and placebo capsules and some funding for packaging.

Why was this study needed?

Cardiovascular disease is the leading cause of death in the UK. It accounted for 152,465 deaths in 2016, of which 66,076 deaths were from coronary heart disease and 37,771 from stroke. Around 4 million people in the UK have diabetes, mostly type 2. Adults with diabetes are two to three times more likely to develop cardiovascular disease, and nearly twice as likely to die from heart disease or stroke, compared with those without diabetes.

It’s well established that aspirin reduces risk in people who have already experienced a heart attack or stroke. However, use as primary prevention for people without established disease is debated. A prior study found that aspirin may slightly reduce heart disease and strokes, but the benefit was outweighed by the bleeding risk.

A group of three trials are investigating the use of aspirin for primary prevention in people with different risk factors, and ASCEND looks at those with diabetes.

What did this study do?

The ASCEND randomised controlled trial included 15,480 UK adults, aged 40 years or over, with any type of diabetes but without known cardiovascular disease. They were assigned to receive 100mg of aspirin daily or matching placebo. They were also assigned to daily capsules containing n−3 fatty acids or matching placebo, the results of which are reported in a companion publication.

Neither participants nor researchers were aware of group allocation. Baseline characteristics and adherence to treatment were equivalent in both groups. Average follow-up was 7.4 years with complete participant follow-up.

The trial had sufficient sample size to detect a 15% difference in the main outcome of a first serious vascular event, defined as a non-fatal heart attack or stroke, transient ischemic attack, or death from a vascular cause.

What did it find?

Fewer people taking aspirin experienced a serious vascular event during follow-up: 8.5% compared with 9.6% taking placebo (rate ratio [RR] 0.88, 95% confidence interval [CI] 0.79 to 0.97). There was no difference in the number of deaths from vascular causes.

However, aspirin similarly increased the number of people who experienced a major bleed: 4.1% compared with 3.2% taking placebo (RR 1.29, 95% CI 1.09 to 1.52), of which 41% were gastrointestinal bleeds. The rate of fatal bleeds was equivalent in both groups (0.2%), as was the rate of haemorrhagic stroke (0.3%).

This gave a close risk-benefit balance: about 91 people with diabetes would need to take aspirin over seven years to prevent one serious vascular event, while treating 112 would cause one major bleed. Put another way, this is approximately one in 100 people experiencing a major benefit and one in 100 people a major harm, on average.

Adjustments for baseline cardiovascular risk made no difference to the comparative rates of vascular events or serious bleeds, nor did use of n−3 fatty acids.

Aspirin did not affect cancer risk, which occurred in 12% of both groups, nor the risk of gastrointestinal cancers, specifically, affecting 2% of both groups.

What does current guidance say on this issue?

The NICE 2015 guideline on the management of type 2 diabetes states that aspirin (or other antiplatelet therapy) should not be offered to adults with type 2 diabetes who do not have cardiovascular disease.

The NICE guideline on cardiovascular disease risk assessment and reduction, recommends using the QRISK2 assessment tool in assessing need for primary prevention in people with type 2 diabetes. Those who score 10% are offered statins in addition to weight management and lifestyle modifications (to diet, physical activity, smoking and alcohol).

In the NICE 2013 guideline on myocardial infarction, daily aspirin is recommended indefinitely as secondary prevention among people who have had an acute coronary syndrome.

What are the implications?

Aspirin protects against further cardiovascular events in people with established cardiovascular disease. Yet despite an increased risk of heart disease and stroke, most people with early diabetes live without these conditions.

But does using aspirin as prevention help these people? The large sample size and long-term follow-up appear to produce a definitive answer. The small benefit of aspirin for primary cardiovascular prevention in diabetes is offset by an equivalent small risk of serious bleeding.

The evidence supports guideline recommendations that aspirin should not be prescribed for primary prevention of cardiovascular disease. Diabetes alone is not sufficient indication. Lifestyle modifications and use of statins, if indicated, should be used to reduce risk.

Citation and Funding

This project was funded by the British Heart Foundation. The aspirin and matching placebo (along with funding for packaging) were provided by Bayer (Germany), while Solvay, Abbott, and Mylan provided the n−3 fatty acid and placebo capsules and some funding for packaging.

Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus

Published on 28 August 2018

ASCEND Study Collaborative Group

N Engl J Med, 2018

Background Diabetes mellitus is associated with an increased risk of cardiovascular events. Aspirin use reduces the risk of occlusive vascular events but increases the risk of bleeding; the balance of benefits and hazards for the prevention of first cardiovascular events in patients with diabetes is unclear. Methods We randomly assigned adults who had diabetes but no evident cardiovascular disease to receive aspirin at a dose of 100 mg daily or matching placebo. The primary efficacy outcome was the first serious vascular event (i.e., myocardial infarction, stroke or transient ischemic attack, or death from any vascular cause, excluding any confirmed intracranial hemorrhage). The primary safety outcome was the first major bleeding event (i.e., intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding). Secondary outcomes included gastrointestinal tract cancer. Results A total of 15,480 participants underwent randomization. During a mean follow-up of 7.4 years, serious vascular events occurred in a significantly lower percentage of participants in the aspirin group than in the placebo group (658 participants [8.5%] vs. 743 [9.6%]; rate ratio, 0.88; 95% confidence interval [CI], 0.79 to 0.97; P=0.01). In contrast, major bleeding events occurred in 314 participants (4.1%) in the aspirin group, as compared with 245 (3.2%) in the placebo group (rate ratio, 1.29; 95% CI, 1.09 to 1.52; P=0.003), with most of the excess being gastrointestinal bleeding and other extracranial bleeding. There was no significant difference between the aspirin group and the placebo group in the incidence of gastrointestinal tract cancer (157 participants [2.0%] and 158 [2.0%], respectively) or all cancers (897 [11.6%] and 887 [11.5%]); long-term follow-up for these outcomes is planned. Conclusions Aspirin use prevented serious vascular events in persons who had diabetes and no evident cardiovascular disease at trial entry, but it also caused major bleeding events. The absolute benefits were largely counterbalanced by the bleeding hazard. (Funded by the British Heart Foundation and others; ASCEND Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).

Expert commentary

The ASCEND Study examined the use of aspirin in people with type 2 diabetes without evidence of cardiovascular disease.

The primary efficacy outcome of a first serious vascular event (myocardial infarction, stroke or transient ischemic attack, or death from any vascular cause, excluding any confirmed intracranial haemorrhage) was significantly lower in those receiving aspirin.

However, this was offset by a significant increase in major bleeding events in the aspirin group. On balance, aspirin should be reserved for secondary prevention of cardiovascular disease in people with type 2 diabetes.